Trophoblastic cell surface antigen 2 (TROP2) is a membrane glycoprotein overexpressed in many solid tumors with a poor prognosis, including intestinal neoplasms. In our study, we show that TROP2 is expressed in preneoplastic lesions, and its expression is maintained in most colorectal cancers (CRC). High TROP2 positivity correlated with lymph node metastases and poor tumor differentiation and was a negative prognostic factor. To investigate the role of TROP2 in intestinal tumors, we analyzed two mouse models with conditional disruption of the adenomatous polyposis coli (Apc) tumor-suppressor gene, human adenocarcinoma samples, patient-derived organoids, and TROP2-deficient tumor cells. We found that Trop2 is produced early after Apc inactivation and its expression is associated with the transcription of genes involved in epithelial-mesenchymal transition, the regulation of migration, invasiveness, and extracellular matrix remodeling. A functionally similar group of genes was also enriched in TROP2-positive cells from human CRC samples. To decipher the driving mechanism of TROP2 expression, we analyzed its promoter. In human cells, this promoter was activated by β-catenin and additionally by the Yes1-associated transcriptional regulator (YAP). The regulation of TROP2 expression by active YAP was verified by YAP knockdown in CRC cells. Our results suggest a possible link between aberrantly activated Wnt/β-catenin signaling, YAP, and TROP2 expression.

• Klíčová slova
• APC, EMT, TACSTD2, WNT/β-catenin signaling, colorectal cancer, expression profiling, organoids,
• Publikační typ
• časopisecké články MeSH

Cells are continuously sensing their microenvironment and subsequently respond to different physicochemical cues by the activation or inhibition of different signaling pathways. To study a very complex cellular response, it is necessary to diminish background environmental influences and highlight the particular event. However, surface-driven nonspecific interactions of the abundant biomolecules from the environment influence the targeted cell response significantly. Yes-associated protein (YAP) translocation may serve as a marker of human hepatocellular carcinoma (Huh7) cell responses to the extracellular matrix and surface-mediated stresses. Here, we propose a platform of tunable functionable antifouling poly(carboxybetain) (pCB)-based brushes to achieve a molecularly clean background for studying arginine, glycine, and aspartic acid (RGD)-induced YAP-connected mechanotransduction. Using two different sets of RGD-functionalized zwitterionic antifouling coatings with varying compositions of the antifouling layer, a clear correlation of YAP distribution with RGD functionalization concentrations was observed. On the other hand, commonly used surface passivation by the oligo(ethylene glycol)-based self-assembled monolayer (SAM) shows no potential to induce dependency of the YAP distribution on RGD concentrations. The results indicate that the antifouling background is a crucial component of surface-based cellular response studies, and pCB-based zwitterionic antifouling brush architectures may serve as a potential next-generation easily functionable surface platform for the monitoring and quantification of cellular processes.

• Klíčová slova
• antifouling polymer brushes, cell mechanotransduction, cell signaling, functional biointerfaces, surface modification, zwitterionic material,
• MeSH
• akrylamidy chemie   MeSH
• biokompatibilní potahované materiály chemie   MeSH
• bioznečištění prevence a kontrola   MeSH
• buněčný převod mechanických signálů * MeSH
• extracelulární matrix metabolismus   MeSH
• lidé MeSH
• mechanický stres MeSH
• nádorové buněčné linie MeSH
• oligopeptidy chemie   MeSH
• protoonkogenní proteiny c-yes metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• akrylamidy MeSH
• arginyl-glycyl-aspartic acid MeSH Prohlížeč
• biokompatibilní potahované materiály MeSH
• oligopeptidy MeSH
• protoonkogenní proteiny c-yes MeSH
• YES1 protein, human MeSH Prohlížeč
• zwitterion carboxybetaine acrylamide MeSH Prohlížeč

Phosphorylation-dependent YAP translocation is a well-known intracellular mechanism of the Hippo pathway; however, the molecular effectors governing YAP cytoplasmic translocation remains undefined. Recent findings indicate that oncogenic YAP paradoxically suppresses Wnt activity. Here, we show that Wnt scaffolding protein Dishevelled (DVL) is responsible for cytosolic translocation of phosphorylated YAP. Mutational inactivation of the nuclear export signal embedded in DVL leads to nuclear YAP retention, with an increase in TEAD transcriptional activity. DVL is also required for YAP subcellular localization induced by E-cadherin, α-catenin, or AMPK activation. Importantly, the nuclear-cytoplasmic trafficking is dependent on the p53-Lats2 or LKB1-AMPK tumor suppressor axes, which determine YAP phosphorylation status. In vivo and clinical data support that the loss of p53 or LKB1 relieves DVL-linked reciprocal inhibition between the Wnt and nuclear YAP activity. Our observations provide mechanistic insights into controlled proliferation coupled with epithelial polarity during development and human cancer.

• MeSH
• adaptorové proteiny signální transdukční metabolismus   MeSH
• aktivní transport - buněčné jádro * MeSH
• alfa-katenin metabolismus   MeSH
• buněčné jádro metabolismus   MeSH
• buňky A549 MeSH
• cytoplazma metabolismus   MeSH
• fosfoproteiny metabolismus   MeSH
• fosforylace MeSH
• HCT116 buňky MeSH
• HEK293 buňky MeSH
• kadheriny metabolismus   MeSH
• kinasy AMP aktivovaných proteinkinas MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• mutace MeSH
• mutační analýza DNA MeSH
• myši nahé MeSH
• myši MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• protein dishevelled metabolismus   MeSH
• protein Wnt1 metabolismus   MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• proteinkinasy aktivované AMP metabolismus   MeSH
• proteiny buněčného cyklu MeSH
• proteiny Wnt metabolismus   MeSH
• signální dráha Hippo MeSH
• signální proteiny YAP MeSH
• transkripční faktory MeSH
• transport proteinů MeSH
• tumor supresorové geny * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• alfa-katenin MeSH
• DVL1 protein, human MeSH Prohlížeč
• fosfoproteiny MeSH
• kadheriny MeSH
• kinasy AMP aktivovaných proteinkinas MeSH
• nádorový supresorový protein p53 MeSH
• protein dishevelled MeSH
• protein Wnt1 MeSH
• protein-serin-threoninkinasy MeSH
• proteinkinasy aktivované AMP MeSH
• proteiny buněčného cyklu MeSH
• proteiny Wnt MeSH
• signální proteiny YAP MeSH
• STK11 protein, human MeSH Prohlížeč
• TP53 protein, human MeSH Prohlížeč
• transkripční faktory MeSH
• WNT1 protein, human MeSH Prohlížeč
• YAP1 protein, human MeSH Prohlížeč
• Yap1 protein, mouse MeSH Prohlížeč

In this review, we address aspects of Wnt, R-Spondin (RSPO) and Hippo signalling, in both healthy and transformed intestinal epithelium. In intestinal stem cells (ISCs), the Wnt pathway is essential for intestinal crypt formation and renewal, whereas RSPO-mediated signalling mainly affects ISC numbers. In human colorectal cancer (CRC), aberrant Wnt signalling is the driving mechanism initiating this type of neoplasia. The signalling role of the RSPO-binding transmembrane proteins, the leucine-rich-repeat-containing G-protein-coupled receptors (LGRs), is possibly more pleiotropic and not only limited to the enhancement of Wnt signalling. There is growing evidence for multiple crosstalk between Hippo and Wnt/β-catenin signalling. In the ON state, Hippo signalling results in serine/threonine phosphorylation of Yes-associated protein (YAP1) and tafazzin (TAZ), promoting formation of the β-catenin destruction complex. In contrast, YAP1 or TAZ dephosphorylation (and YAP1 methylation) results in β-catenin destruction complex deactivation and β-catenin nuclear localization. In the Hippo OFF state, YAP1 and TAZ are engaged with the nuclear β-catenin and participate in the β-catenin-dependent transcription program. Interestingly, YAP1/TAZ are dispensable for intestinal homeostasis; however, upon Wnt pathway hyperactivation, the proteins together with TEA domain (TEAD) transcription factors drive the transcriptional program essential for intestinal cell transformation. In addition, in many CRC cells, YAP1 phosphorylation by YES proto-oncogene 1 tyrosine kinase (YES1) leads to the formation of a transcriptional complex that includes YAP1, β-catenin and T-box 5 (TBX5) DNA-binding protein. YAP1/β-catenin/T-box 5-mediated transcription is necessary for CRC cell proliferation and survival. Interestingly, dishevelled (DVL) appears to be an important mediator involved in both Wnt and Hippo (YAP1/TAZ) signalling and some of the DVL functions were assigned to the nuclear DVL pool. Wnt ligands can trigger alternative signalling that directly involves some of the Hippo pathway components such as YAP1, TAZ and TEADs. By upregulating Wnt pathway agonists, the alternative Wnt signalling can inhibit the canonical Wnt pathway activity.

• Klíčová slova
• Hippo pathway, LGR, R-Spondins, Wnt/β-catenin signalling, YAP1/TAZ, colorectal cancer,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The toxicity of environmental and dietary ligands of the aryl hydrocarbon receptor (AhR) in mature liver parenchymal cells is well appreciated, while considerably less attention has been paid to their impact on cell populations exhibiting phenotypic features of liver progenitor cells. Here, we discuss the results suggesting that the consequences of the AhR activation in the cellular models derived from bipotent liver progenitors could markedly differ from those in hepatocytes. In contact-inhibited liver progenitor cells, the AhR agonists induce a range of effects potentially linked with tumor promotion. They can stimulate cell cycle progression/proliferation and deregulate cell-to-cell communication, which is associated with downregulation of proteins forming gap junctions, adherens junctions, and desmosomes (such as connexin 43, E-cadherin, β-catenin, and plakoglobin), as well as with reduced cell adhesion and inhibition of intercellular communication. At the same time, toxic AhR ligands may affect the activity of the signaling pathways contributing to regulation of liver progenitor cell activation and/or differentiation, such as downregulation of Wnt/β-catenin and TGF-β signaling, or upregulation of transcriptional targets of YAP/TAZ, the effectors of Hippo signaling pathway. These data illustrate the need to better understand the potential role of liver progenitors in the AhR-mediated liver carcinogenesis and tumor promotion.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH